During the previous grant periods we developed an extensive genetic and environmental AMD database including large families, multiplex families with affected and unaffected siblings and affected and discordant sib-pairs, affected children and unaffected children, in addition to well-characterized unrelated cases and controls. We also developed a DNA, serum and plasma repository for these subjects. We reported the following: identification of several areas of genetic linkage in our family-based sample;identification of a novel variant in the complement factor H (CFH) gene in our case-control sample;confirmation of other variants in the CFH and LOC387715/HTRA1 gene regions;first confirmation of the variants in the BF/C2 regions;and report of the independent effects of both the common CFH coding polymorphism and environmental factors, smoking and body mass index, including an interaction between CFH and body mass index, while simultaneously controlling for both genetic and environmental factors, and a major review of AMD genetics. We also published the description and evaluation of our Clinical Age-Related Maculopathy Grading System which has been used throughout the last two grant periods. During this next grant period, we propose to build upon this foundation using our well characterized study databases with the goal of finding additional gene or genes associated with susceptibility to various stages of AMD, as well as disease progression, and associations between genetic variants and biologic and environmental factors. We will apply the methodologies of large scale family-based association studies, population-based case-control association studies, prospective cohort analyses, and an expanded genome-wide family-based linkage study conditional on known gene variants for this project. To accomplish these goals, we will complete the ascertainment of enrolled families as well as complete the recruitment of cases and controls, complete risk factor data collection and acquisition of blood specimens, and prospectively update AMD status of siblings, children, and unrelated subjects to assess factors associated with AMD progression. The overall goal is to translate knowledge gained into useful clinical information relevant to patient management, prevention, and better therapies, and to reduce visual loss due to this prevalent disease. This project is responsive to the mission of NEI, by addressing the "pathophysiologic heterogeneity of AMD" and the "roles of the environment and genetics in risk factors for retinal disease" which will lead to better "genotype/phenotype- environment correlations for the study of disease progression" and also "improved diagnosis, prevention, and therapy".